PIKfyve, a Class III Lipid Kinase, Is Required for TLR-Induced Type I IFN Production via Modulation of ATF3

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Type I IFN plays a key role in antiviral responses. It also has been shown that deregulation of type I IFN expression following abnormal activation of TLRs contributes to the pathogenesis of systemic lupus erythematosus. In this study, we find that PIKfyve, a class III lipid kinase, is required for endolysosomal TLR-induced expression of type I IFN in mouse and human cells. PIKfyve binds to phosphatidylinositol 3-phosphate and synthesizes phosphatidylinositol 3,5-bisphosphate, and plays a critical role in endolysosomal trafficking. However, PIKfyve modulates type I IFN production via mechanisms independent of receptor and ligand trafficking in endolysosomes. Instead, pharmacological or genetic inactivation of PIKfyve rapidly induces expression of the transcription repressor ATF3, which is necessary and sufficient for suppression of type I IFN expression by bin'ding to its promoter and blocking its transcription. Thus, we have uncovered a novel phosphoinositide-mediated regulatory mechanism that controls TLR-mediated induction of type I IFN, which may provide a new therapeutic indication for the PIKfyve inhibitor.
Publisher
AMER ASSOC IMMUNOLOGISTS
Issue Date
2014-04
Language
English
Article Type
Article
Keywords

SYSTEMIC-LUPUS-ERYTHEMATOSUS; ACTIVATING TRANSCRIPTION FACTOR-3; PHOSPHATIDYLINOSITOL 3,5-BISPHOSPHATE; IL-12/IL-23 INHIBITOR; INTERFERON-ALPHA; PROTEIN-KINASE; CPG DNA; TOLL-LIKE-RECEPTOR-4; NEURODEGENERATION; PI(3,5)P-2

Citation

JOURNAL OF IMMUNOLOGY, v.192, no.7, pp.3383 - 3389

ISSN
0022-1767
DOI
10.4049/jimmunol.1302411
URI
http://hdl.handle.net/10203/240794
Appears in Collection
MSE-Journal Papers(저널논문)
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